Aurora A is a member of serine-threonine kinases, and is widely involved in, for example, the formation and maturation of centrosomes, spindle dynamics, and chromosome alignment in the mitotic phase (M phase) of the cell cycle, thereby regulating the progression of mitosis (Non Patent Document 1). So far, overexpression and/or amplification of aurora A have been confirmed in a wide variety of carcinomas (Non Patent Document 2). Also, since inhibition of aurora A kinase in tumor cells induces not only termination of mitosis, but also apoptosis, aurora A is one of the important target molecules in cancer therapy.
Meanwhile, microtubule-targeting agents as represented by taxane and vinca alkaloid are widely used as the key drug in cancer chemotherapy. However, persistent and adequate therapeutic effects are not always obtained due to loss of responsiveness to drugs or becoming resistance to drugs. Therefore, there is clinical need for development of a drug capable of potentiating the anti-tumor effect of taxane drugs since such a drug promises to provide more effective therapeutic opportunities. The cytocidal effect of taxane anticancer agents requires activation of the spindle assembly checkpoint in the cell cycle, and there is a report that tumor cells having a reduced spindle assembly checkpoint activity show reduced sensitivity to taxane anticancer agents (Non Patent Document 3). In addition, it is known that a cell line overexpressing aurora A becomes resistance to paclitaxel (Non Patent Document 4) and inhibition of aurora A potentiates the activity of paclitaxel or docetaxel (Non Patent Document 5). Meanwhile, it has been reported that although aurora B, which is a subtype thereof, shows activity on the mitotic phase (M phase) of the cell cycle with aurora A, inhibition of aurora B reduces the spindle assembly checkpoint activity (Non Patent Document 6). Therefore, it is suggested that the inhibition of aurora B might attenuate the effect of taxane drugs. Also, aurora C is strongly expressed in, for example, testis or germ cells, and the results of human genome analysis have shown that aurora C is important in Spermatogenesis (Non Patent Document 7). The aurora C is known to function as complementation to the function of aurora B in cell division (Non Patent Document 8). Similarly to inhibition of aurora B, inhibition of aurora c induces aneuploidy in cells, leading to exhibiting phenotype which greatly differs from that exhibited by inhibition of aurora A, and potentiation of the effect of taxane drugs cannot presumably be expected. Furthermore, influence on the reproductive system cannot be overlooked, and therefore, it is desirable that the drug does not exhibit the inhibitory activity on aurora C.
According to above, it is expected that by administering a drug which selectively inhibits aurora A kinase in combination with a taxane anticancer agent, the drug will effectively potentiate the anti-tumor activity of the taxane anticancer agent, thereby enabling higher therapeutic effects.
Also, there is a report that the cell cycle termination activity induced by paclitaxel is sustained for several days in a mouse tumor model into which a human cancer cell line is transplanted (Non Patent Document 9). Therefore, an agent for oral administration is considered to be desirable when an aurora A inhibitor is to concomitantly administered, because of enabling continuous exposure.
So far, it has been reported that an aminopyridine derivative exhibiting the inhibitory activity on aurora A can be orally administered (Patent Document 1). However, although Patent Document 1 describes the inhibitory activity on aurora A and on cell proliferation in vitro, any descriptions relating to the evaluation of oral administration of the above compound are not found.